JP2005525308A5

JP2005525308A5 -

Info

Publication number: JP2005525308A5
Application number: JP2003557529A
Authority: JP
Filing date: 2003-01-07
Publication date: 2006-03-02
Anticipated expiration: 2023-01-07

Claims

Acute, subacute or chronic compared to peripheral blood insulin concentrations obtained by subcutaneous injection while containing unmodified insulin doses that achieve a comparable drop in blood glucose concentration in human diabetic patients compared to subcutaneous insulin injection in those patients An oral solid dosage form that provides a lower insulin concentration in the peripheral blood circulation under conditions of

The oral solid dosage form of claim 1, wherein the plasma insulin concentration after oral administration is at least about 20% lower.

Contains an unmodified insulin dose that achieves an effective reduction in blood glucose treatment after oral administration to human diabetics, and provides a portal insulin concentration to peripheral blood ratio of about 2.5: 1 to about 6: 1 Oral dosage form.

The oral dosage form of claim 3, wherein the dosage form is solid.

An oral dosage form containing an unmodified insulin dose that achieves an effective reduction in blood glucose treatment after oral administration to a human diabetic patient, wherein the oral solid dosage form is about 0.25 to An oral dosage form that provides insulin t _max at a time of about 1.5 hours, wherein a decrease in blood glucose concentration of at least about 80% is caused by the insulin dose occurring within about 2 hours after oral administration of the dosage form.

An oral dosage form containing a therapeutically effective amount of unmodified insulin, wherein the dosage form is administered orally prior to oral administration to a human diabetic patient compared to the mean baseline (fasted) plasma glucose concentration in the patient An oral dosage form that results in an average plasma glucose concentration in the patient that is lowered in the first hour after.

An oral dosage form containing a therapeutically effective amount of unmodified insulin, wherein the oral dosage form is the first hour after oral administration relative to the mean baseline (fasting) plasma glucose concentration in the patient when administered pre-meal Providing an average plasma glucose concentration that does not vary by more than about 40%, wherein a meal is ingested by the patient within about 30 minutes of oral administration of the dosage form.

8. The oral dosage form of claim 7, which provides an average plasma glucose concentration that does not vary by more than about 30% for the first hour after oral administration.

Insulin t _max is reached at about 0.25 to about 1.5 hours after oral administration to human diabetic patients, and about 40% for the first hour after oral administration from baseline (fasting) plasma glucose concentration in patients. Provide effective management of dietary blood glucose levels during pre-medication administration to patients, as evidenced by providing plasma glucose concentrations that do not fluctuate beyond, and to patients by 4 hours after oral administration An oral solid dosage form containing an insulin dose that provides recovery to baseline blood insulin levels.

10. An oral dosage form according to claim 9, wherein the insulin is human standard insulin type.

The oral dosage form according to any one of claims 1 to 10, wherein the oral dosage form is solid.

12. The oral dosage form according to claim 11, wherein the oral dosage form is in the form of a tablet or capsule.

12. The oral solid dosage form of claim 11, wherein the unmodified insulin dose contained in the dosage form is about 50 units to about 600 units (about 2 to about 23 mg).

The oral solid dosage form of claim 1, which provides a t _max of insulin from about 0.1 to about 1.5 hours after oral administration.

15. The oral dosage according to any of claims 1-14, wherein the dosage form initiates insulin delivery into the portal circulation (absorption through the gastric mucosa) and reaches peak levels within about 30 minutes or less. Solid dosage form.

16. The oral solid dosage form according to any one of claims 1 to 15, further comprising an effective amount of a delivery substance of the following formula or a pharmaceutically acceptable salt thereof:

(Where
X is hydrogen or halogen;
R is substituted or unsubstituted C ₁ -C ₃ alkylene, substituted or unsubstituted C ₁ -C ₃ alkenylene, substituted or unsubstituted C ₁ -C ₃ alkyl (arylene), substituted or unsubstituted C _1- C ₃ aryl (alkylene). ).

The oral solid dosage form of claim 16, wherein X is a halogen.

18. An oral solid dosage form pharmaceutical composition according to claim 17, wherein the halogen is chlorine.

R is a C ₃ alkylene, oral solid dosage form of claim 16, wherein.

17. The oral solid dosage form of claim 16, wherein the peak plasma delivery substance concentration occurs within 2 hours of oral administration.

17. The oral solid dosage form according to claim 16, wherein the delivery substance is 4-[(4-chloro, 2-hydroxybenzoyl) amino] butyric acid.

17. The oral solid dosage form of claim 16, which provides a peak plasma delivery substance concentration of about 5,000 to about 15,000 ng / ml within about 0.3 to about 1.5 hours after oral administration.

17. The oral solid dosage form of claim 16, wherein the oral solid dosage form produces a maximum reduction in blood glucose in the treated patient about 20-60 minutes after oral administration.

24. The oral solid dosage form of any one of claims 1-23, wherein the composition produces a maximum decrease in C peptide concentration in a treated patient about 80-120 minutes after oral administration.

25. The oral solid dosage form according to any one of claims 1 to 24, wherein in human patients, serum glucose is reduced by at least 10% within 1 hour after oral administration.

26. The treatment of impaired glucose tolerance, achievement of glucose homeostasis, initial treatment comprising administering the oral dosage form of any one of claims 1 to 25 to a human patient on a chronic basis to achieve an effective reduction of blood glucose. Use of insulin for the manufacture of a medicament for the treatment of diabetes or the treatment of late stage diabetes.

A method for providing an orally administrable unit dose effective for the treatment of unmodified insulin, wherein about 2 to about 23 mg of unmodified insulin is pharmaceutically acceptable to promote absorption of the insulin from the gastrointestinal tract of human diabetic patients A method comprising: combining with about 100 to about 600 mg of a delivery substance, and orally administering the unit dose to a human diabetic patient to provide a therapeutic effect.

Oral dosage forms containing an effective amount of insulin before meals are orally administered to human diabetic patients, resulting in insulin t _max at about 0.25 to about 1.5 hours after oral administration, and the patient's blood glucose concentration is Effective in response to a diet, as demonstrated by providing a plasma glucose concentration that does not vary by more than about 40% for the first hour after oral administration from the baseline (fasted) plasma glucose concentration in the patient Use of insulin for the manufacture of a medicament for the treatment of human diabetic patients, which is controlled and includes providing a recovery of the patient to baseline blood insulin levels by 4 hours after oral administration.

Diabetic patients to provide a therapeutically effective reduction in blood glucose and peak plasma insulin concentrations that are reduced compared to a therapeutically effective peak plasma insulin concentration equivalent to the blood glucose concentration achieved by subcutaneous insulin injection Insulin for the manufacture of a medicament for the treatment of diabetes, comprising the step of orally administering an oral insulin treatment containing an unmodified insulin dose together with a delivery substance that promotes absorption of insulin from the gastrointestinal tract on a chronic basis Use of.

A diabetic patient is orally administered on a chronic basis with an insulin dose and a delivery substance that facilitates absorption of this insulin dose from the gastrointestinal tract, and is effective for therapeutic management and / or lowering blood glucose levels, and blood of a human diabetic population. Providing an average systemic blood insulin concentration in a diabetic patient that is reduced compared to an average systemic blood insulin concentration provided by subcutaneous injection of an amount of insulin effective to achieve an equivalent management and / or reduction in glucose concentration. Use of insulin to produce a medicament for reducing the occurrence and severity of hyperinsulinemia associated with chronic insulin administration.

32. Use according to claim 30, wherein the occurrence of a pathological condition associated with chronic administration of insulin is reduced as a result of the chronic administration.

Diabetic patients are treated by chronic oral administration with a therapeutically effective amount of a pharmaceutical composition containing insulin and a delivery substance that promotes absorption of the insulin from the gastrointestinal tract, so that the pharmaceutical composition is administered by subcutaneous injection of insulin. Insulin comprising the steps of providing an effective reduction in the treatment of blood glucose and peak serum insulin concentrations in a diabetic patient that is reduced relative to a therapeutically effective reduction in peak serum insulin concentration equivalent to the achieved blood glucose concentration Use of insulin for the manufacture of a medicament for the occurrence and / or reduction of the severity of one or more pathologies associated with chronic administration of.

Oral administration provides a reduced expression of a gene associated with vascular disease compared to the level of gene expression associated with vascular disease resulting from an equivalent reduction in blood glucose concentration achieved in a patient population by subcutaneous injection of insulin; Use according to any one of claims 29 to 32.

34. Use according to claim 33, wherein the gene associated with vascular disease is selected from the group consisting of early response genes, cytokine-related genes, adhesion molecule-related genes, lipid peroxidation-related genes, thrombosis-related genes and combinations thereof.

35. Use according to claim 34, wherein the early response gene is selected from the group consisting of c-myc, jun B, Egr-1, Ets-1, and combinations thereof.

The plasminogen activator inhibitor concentration resulting from the method is lower compared to a plasminogen activator inhibitor concentration resulting from a therapeutically effective drop equivalent to a blood glucose concentration achieved by subcutaneous insulin injection. Use according to 29-32.

33. The proinflammatory cytokine concentration resulting from the method is lower compared to the proinflammatory cytokine concentration resulting from an equivalent therapeutically effective reduction in blood glucose concentration achieved by subcutaneous injection of insulin. Use of any one of Claims.

The use according to any one of claims 31 to 33, wherein the pathological condition is cardiovascular disease.

34. Use according to any one of claims 31 to 33, wherein the pathology is selected from the group consisting of neuropathy, nephropathy, retinopathy, arteropathy, atherosclerosis and combinations thereof.

34. Use according to any one of claims 31 to 33, wherein the pathology is selected from the group consisting of coronary artery disease, hypertensive cardiomyopathy and congestive heart failure.

A compound wherein the delivery substance has the formula:

Or use according to any one of claims 27 to 33, which is or a pharmaceutically acceptable salt thereof:
(In the formula
X is hydrogen or halogen;
R is substituted or unsubstituted C ₁ -C ₁₂ alkylene, substituted or unsubstituted C ₁ -C ₁₂ alkenylene. ).

42. Use according to claim 41, wherein the delivery substance is 4-[(4-chloro, 2-hydroxybenzoyl) aminobutyric acid or a derivative or analogue thereof.

33. Use according to any one of claims 28 to 32, wherein the insulin contained in the oral dosage form is human standard insulin type.

33. Use according to any one of claims 28 to 32, wherein the insulin is selected from the group consisting of recombinant human insulin, bovine insulin, porcine insulin and functional equivalents thereof.

Orally administering an oral insulin treatment containing a dosage of insulin on a chronic basis to a diabetic patient together with a delivery substance that facilitates absorption of the insulin from the gastrointestinal tract, thereby reducing the blood glucose level in the diabetic patient by a desired amount, The insulin concentration circulating in the blood of the diabetic as a result of insulin treatment is reduced compared to a therapeutically reduced peak serum insulin concentration equivalent to the blood glucose concentration achieved by subcutaneous injection of insulin Use of insulin to produce a medicament for the development, severity, or reduction of occurrence and severity of a disease state or vascular disease associated with chronic insulin administration to diabetes.

Orally administering an oral insulin treatment containing a dosage of insulin on a chronic basis to a diabetic patient together with a delivery substance that facilitates absorption of the insulin from the gastrointestinal tract, thereby reducing the blood glucose level of the diabetic patient by a desired amount, The insulin concentration circulating in the blood of the diabetic as a result of insulin treatment is reduced compared to a therapeutically reduced peak serum insulin concentration equivalent to the blood glucose concentration achieved by subcutaneous injection of insulin Use of insulin to produce a medicament for reducing exposure of a diabetic patient to a hyperinsulinemia state of the vasculature.

Orally administering an oral insulin treatment containing a dosage of insulin on a chronic basis to a diabetic patient together with a delivery substance that facilitates absorption of the insulin from the gastrointestinal tract, thereby reducing the blood glucose level of the diabetic patient by a desired amount, The insulin concentration circulating in the blood of the diabetic as a result of insulin treatment is reduced compared to a therapeutically reduced peak serum insulin concentration equivalent to the blood glucose concentration achieved by subcutaneous injection of insulin Use of insulin to produce a medicament for a method that attenuates the process resulting from response to mild injury stimuli in multiple regions in response to increased mRNA during insulin treatment.

Orally administering an oral insulin treatment containing a dosage of insulin on a chronic basis to a diabetic patient together with a delivery substance that facilitates absorption of the insulin from the gastrointestinal tract, thereby reducing the blood glucose level of the diabetic patient by a desired amount, Insulin for producing a medicament for the treatment of diabetics, comprising the fact that the concentration of insulin circulating in the blood of the diabetic as a result of insulin treatment is not substantially higher than normal physiological levels use.

Drug screening methods for vascular injury related to the route of drug administration:
Administering the drug parenterally to the first subject animal;
Orally administering the drug to the second test animal, and the first and second test animals are selected from the group consisting of c-myc, c-fos, Jun B, Erg-1 and combinations thereof Comparing the expression of early response genes, wherein increased expression of one or more early response genes is an indicator of vascular injury.

50. The method of claim 49, wherein measuring the change in expression comprises gene chip analysis.

50. The method of claim 49, wherein measuring the change in expression comprises measuring the change in mRNA expression.